Role of transplanted bone marrow cells in development of rotator cuff muscle fatty degeneration in mice

2017 ◽  
Vol 26 (12) ◽  
pp. 2177-2186 ◽  
Author(s):  
Lawrence V. Klomps ◽  
Naseem Zomorodi ◽  
H. Mike Kim
Keyword(s):  
Bone Marrow ◽  
Rotator Cuff ◽  
Bone Marrow Cells ◽  
Fatty Degeneration ◽  
Rotator Cuff Muscle ◽  
Marrow Cells

scholarly journals THE ROLE OF THYMUS AND BONE MARROW CELLS IN DELAYED HYPERSENSITIVITY

1971 ◽  
Vol 134 (5) ◽  
pp. 1144-1154 ◽  
Author(s):  
David G. Tubergen ◽  
Joseph D. Feldman
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Cells ◽  
Specific Antigen ◽  
Delayed Hypersensitivity ◽  
Cell Type ◽  
Skin Reactions ◽  
Lymph Node Cells ◽  
Thymus Cells ◽  
Marrow Cells

Adoptive transfer experiments were performed to define the immunological role of thymus and bone marrow cells in the induction of delayed hypersensitivity (DH). The results indicated the following, (a) Bone marrow from immune donors contained cells capable of being stimulated by antigen to initiate the expression of DH. (b) Bone marrow from nonimmune or tolerant donors contained cells that were needed to complete the expression of DH after the infusion of immune lymph node cells. (c) Normal bone marrow and thymus cells cooperated in the irradiated recipient to induce the most vigorous skin reactions to specific antigen; these reactions were seen only when the recipients were stimulated by antigen. Either cell type alone was ineffective. (d) In the presence of tolerant bone marrow cells, thymus cells from immune donors gave a more vigorous response than did thymus cells from normal or tolerant donors. (e) There was suggestive evidence that thymus cells were the source of trigger elements that initiated DH. (f) Antigen in the irradiated recipient was necessary to induce DH after infusion of bone marrow cells alone, or bone marrow and thymus cells together.

scholarly journals Pivotal Role of OCL-Derived IGF1 in Drug Resistance and Bone Destruction in MM

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4336-4336
Author(s):  
Jumpei Teramachi ◽  
Kazuaki Miyagawa ◽  
Delgado-Calle Jesus ◽  
Jolene Windle ◽  
Noriyoshi Kurihara ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Drug Resistance ◽  
Bone Resorption ◽  
Bone Marrow Cells ◽  
Critical Role ◽  
Bone Destruction ◽  
Bone Marrow Microenvironment ◽  
Rank Ligand ◽  
Marrow Cells

Multiple myeloma (MM) is largely incurable, and is characterized by devastating bone destruction caused by increased osteoclast (OCL) differentiation and bone resorption in more than 85% of MM patients. OCLs in MM not only promote bone resorption but also increase MM cell growth and drug resistance. Despite recent advances in anti-myeloma treatment, development of anti-MM drug resistance is a major limitation of MM therapy. Therefore, new treatment modalities are urgently needed to overcome drug resistance and decrease bone resorption. IGF1 is a crucial factor for tumor cell growth and survival of malignant cells, especially in MM. IGFI also contributes to development of drug resistance of MM cells to anti-MM agents, including proteasome inhibitors and immunomodulatory agents, but how OCLs contribute to drug resistance is still not clearly delineated. We found that IGF1 was highly expressed in OCLs attached to bone and bone marrow myeloid cells in vivo, and the expression levels of IGF1 in OCLs from MM bearing mice is higher than in normal OCLs. Intriguingly, OCLs produced more IGF1 (0.8 ng/ml/protein) than MM cells (not detected) and bone marrow stromal cells (BMSCs) (0.4 ng/ml/protein) in vitro. In addition, IGF1 protein expression in OCLs was upregulated (1.8 fold) by treatment with conditioned media (CM) from 5TGM1 murine MM cells, TNF-α or IL-6, major paracrine factors that are increased in the bone marrow microenvironment in MM. These results suggest that OCLs are a major source of local IGF1 in the MM bone marrow microenvironment. To further characterize the role of OCL-derived IGF1, we generated a novel mouse with targeted deletion of Igf1 in OCLs (IGF1-/--OCL), and assessed the role of OCL-derived IGF1 in drug resistance of MM cells and bone destruction. Treatment of 5TGM1 cells with bortezomib (BTZ) (3 nM, 48 hours) decreased the viability of 5TGM1 cells by 50%. Importantly, the cytotoxic effects of BTZ on MM cells were decreased (by 5%) when MM cells were cocultured with OCLs from wild type (WT) mice. In contrast, coculture of MM cells with IGF1-/--OCLs or WT-OCLs treated with IGF1 neutralizing antibody (IGF1-ab) did not block BTZ's effects on MM cell death. Consistent with these results, coculture of MM cells with IGF1-/--OCLs or WT-OCLs treated with IGF1-ab resulted in BTZ-induced caspase-dependent apoptosis in MM cells. We next examined the effects of OCLs on the signaling pathways responsible for MM cell survival. WT-OCL-CM promptly induced the phosphorylation of Akt and activation of p38, ERK and NF-κB in MM cells. However, these pathways were not activated by MM cells treated with IGF1-/--OCL-CM or IGF1-ab-treated WT-OCL-CM. Since adhesion of MM cells to BMSCs via interaction of VLA-4 and VCAM-1 plays a critical role in cell adhesion-mediated drug resistance (CAMDR) in MM, we tested if treatment of human BMSCs with human OCL-CM upregulated VCAM-1 expression. We found that OCL-CM upregulated VCAM-1 expression on BMSCs (x fold). In contrast, treatment of BMSCs with OCLs treated with IGF1-ab blocked VCAM-1 induction. These data suggest that OCL-derived IGF1 can contribute to MM cell drug resistance in the bone marrow microenvironment. We then examined the role of IGF1 inhibition on osteoclastogenesis and the bone resorption capacity of OCLs. RANK ligand induced the expression of cathepsin K and NFATc1 in CD11b+ bone marrow cells from WT mice, differentiation markers of OCLs, and the formation of TRAP-positive multinucleated OCLs. However, OCLs formed by RANK ligand treatment of CD11b+ bone marrow cells from IGF1-/- mice had markedly decreased cathepsin K and NFATc1 expression and OCL formation. Next, we tested the bone resorption capacity of OCLs formed by CD11b+ bone marrow cells from IGF1-/- mice vs. WT mice. Similar numbers of OCLs were cultured with RANK ligand on bone slices for 72 hours. The bone resorption activity of Igf1-/--OCLs was significantly decreased (70%) compared with WT-OCLs. These results suggest that OCL-derived IGF1 plays a critical role in MM drug resistance and bone destruction, and that inhibition of the effect of IGF1 in OCLs should decrease MM drug resistance and bone destruction. Disclosures Roodman: Amgen trial of Denosumab versus Zoledronate: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees.

The role of bone marrow cells for JCV pathogenicity

2009 ◽  
Vol 45 (3) ◽  
pp. 230-231 ◽  
Author(s):  
Daniele Focosi ◽  
Fabrizio Maggi ◽  
Elisabetta Andreoli ◽  
Letizia Lanini ◽  
Luca Ceccherini-Nelli ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Cells ◽  
Marrow Cells

scholarly journals The Role of Bone Marrow Cells in the Phenotypic Changes Associated with Diabetic Nephropathy

PLoS ONE ◽  
2015 ◽  
Vol 10 (9) ◽  
pp. e0137245 ◽  
Author(s):  
Guang Yang ◽  
Qingli Cheng ◽  
Sheng Liu ◽  
Jiahui Zhao
Keyword(s):  
Bone Marrow ◽  
Diabetic Nephropathy ◽  
Bone Marrow Cells ◽  
Phenotypic Changes ◽  
Marrow Cells

Overlapping but Distinct Role of p21WAF1/CDKN1 and Survivin in Hematopoietic Progenitor Cell Proliferation.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1334-1334
Author(s):  
Seiji Fukuda ◽  
Mariko Abe ◽  
Seiji Yamaguchi ◽  
Louis M. Pelus
Keyword(s):  
Cell Cycle ◽  
Bone Marrow ◽  
Cell Proliferation ◽  
Growth Factor ◽  
Bone Marrow Cells ◽  
Mouse Bone Marrow ◽  
Hematopoietic Progenitor ◽  
Primary Mouse ◽  
Marrow Cells

Abstract Survivin is a member of the inhibitor of apoptosis protein family that has been implicated in cell cycle control, anti-apoptosis and cell division. Our previous studies and others have shown that Survivin and the cyclin dependent kinase inhibitor p21WAF1/CDKN1 (p21) are functionally associated and are involved in cell cycle, anti-apoptosis and cytokinesis in cancer cells and in normal hematopoietic progenitor cells (HPC). P21 is highly expressed in quiescent hematopoietic stem cells (HSC) in steady state, but the proportion of quiescent HSCs in G0 phase is reduced in p21−/− mice. In contrast, p21 has been shown as positive regulator on cell cycle of normal HPC since p21 deficiency results in fewer total CFU in mouse bone marrow (BM) cells with fewer CFU in S-phase and retrovirus transduction of p21 in p21 deficient bone marrow cells restores total and cycling CFU. We have previously reported that Survivin increases the proliferation of mouse primary HPC and that this enhancing effect is on HPC proliferation is absent when p21 is functionally deleted, suggesting that p21 is required for Survivin to enhance HPC proliferation. In addition, ITD-Flt3 mutations that are normally expressed in patients with acute myeloid leukemia and associate poor prognosis increase expression of both Survivin and p21, implicating their involvement in aberrant proliferation of HPC expressing ITD-Flt3. Herein we have characterized the functional association between p21 and Survivin in normal and transformed cell proliferation. Antagonizing wild-type Survivin in mouse BaF3 cells by retrovirus transduction of a T34A dominant negative mutant Survivin or anti-sense increased p21 expression, even though Survivin requires p21 to enhance HPC proliferation. Ectopic p21 in Survivin+/+ primary mouse bone marrow cells increased the number of immunophenotypically defined c-kit+, lin− (KL) cells, which is consistent with a positive role of p21 in HPC proliferation, however; ectopic expression of p21 failed to increase HPC proliferation in Survivin deficient primary bone marrow cells, suggesting that p21 alone is not sufficient to substitute for Survivin’s enhancing function on normal HPC proliferation. Over-expression of ITD-Flt3 enhanced growth factor independent proliferation of primary mouse marrow c-kit+, Sca-1+, lin− (KSL) cell number; however, co-expression of p21 with ITD-Flt3 dramatically decreased the number of growth factor independent KSL cells (80±6% reduction: P<0.01). Furthermore, the inhibitory effect of p21 on KLS proliferation was further enhanced by Survivin knockout bone marrow cells (64±5% reduction compared with presence of Survivin: P<0.05). These findings indicate that Survivin and p21 have a overlapping but distinct roles in regulating normal HPC proliferation and that manipulating p21 and Survivin may represent a potential therapeutic target for acute leukemia cells expressing ITD-Flt3.

Direct Binding of Grb2 Is Required for Efficient Induction of Myeloproliferative Disease in Mice by ETV6/FLT3.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2903-2903
Author(s):  
Kazuhisa Chonabayashi ◽  
Masakatsu Hishizawa ◽  
Shin Kawamata ◽  
Masashi Matsui ◽  
Tatsuharu Ohno ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Tyrosine Kinase ◽  
Binding Sites ◽  
Bone Marrow Cells ◽  
Myeloproliferative Disease ◽  
Juxtamembrane Domain ◽  
Murine Bone Marrow ◽  
Direct Binding ◽  
Marrow Cells

Abstract Abstract 2903 Poster Board II-879 FMS-like tyrosine kinase 3 (FLT3), a class III receptor tyrosine kinase, is one of the most frequently mutated genes in hematological malignancies. The most common mutations of FLT3 are internal tandem duplications (ITDs) within the juxtamembrane domain: these mutations occur in 20% to 30% of patients with AML and are closely associated with a poor prognosis. In a small number of patients with myeloproliferative neoplasms (MPNs), FLT3 has been reported to fuse to ETV6 (TEL) and contribute to leukemogenesis, but the leukemogenic mechanism of ETV6/FLT3 remains unclear. We encountered a case of ETV6/FLT3 fusion in a patient with MPN complicated with T-cell lymphoblastic lymphoma. In this case, both myeloid and lymphoma cells shared the same chromosomal translocation, t(12;13)(p13;q12), and allogeneic hematopoietic stem cell transplantation led to complete remission for 3 years. Full-length ETV6/FLT3 fusion cDNA was cloned from the patient's bone marrow cells. Sequence analysis of the PCR product revealed that, in contrast to the finding of previously reported two cases of ETV6/FLT3-positive MPN, ETV6 exon 6 was fused to FLT3 exon 14 and that the fused portion of ETV6 contained 2 potential Grb2-binding sites (Vu et al., Leukemia 2006; Walz et al., Blood 2007a). The ETV6/FLT3 conferred IL-3-independent growth to Ba/F3 and 32Dcl3 cells. Using a dominant negative approach, we showed that both STAT5 and Ras played important roles in ETV6/FLT3-mediated transformation of the hematopoietic cell lines. To investigate the role of the ETV6/FLT3 fusion protein in vivo, we used a murine bone marrow transplant model. Retroviral transduction of the ETV6/FLT3 into primary murine bone marrow cells resulted in a CML-like myeloproliferative disease (MPD) with complete penetrance in the transplanted mice. The disease progressed to cause death at a median of 18 days after transplantation (n = 16). The transplanted mice developed severe leukocytosis (159 × 103 /μl to 417 × 103 /μl), splenomegaly, and extensive infiltration of myeloid cells in the bone marrow, spleen, liver, and peripheral blood. ETV6/FLT3-induced MPD was oligoclonal and only 2 of the 9 secondary transplant recipients developed similar MPD when 5 × 106 spleen cells from 3 independent diseased mice were used as donors. We assayed the mutant forms of the ETV6/FLT3 to test their ability to transform hematopoietic cells. Induction of MPD required the oligomerization domain of ETV6 and the tyrosine kinase activity of FLT3. Mice that received the double tyrosine-to-phenylalanine mutant of ETV6/FLT3 at sites 589 and 591 (Y589/591F) in the juxtamembrane domain of FLT3, which are critical for FLT3-ITD-induced MPD, also developed a similar MPD phenotype. Unlike FLT3-ITDs, Y589/591F mutation did not abrogate STAT5 activation in Ba/F3 and 32Dcl3 cells transformed by ETV6/FLT3. A recent study has shown that direct binding of Grb2 to tyrosine 768, 955, and 969 of FLT3 is important for FLT3-ITD-mediated proliferation and survival of hematopoietic cells. Tyrosine 314 in exon 5 of ETV6 has also been reported as the principal Grb2-binding site that contributes to leukemogenesis via oncogenic ETV6 fusion proteins such as ETV6/ABL. Thus, we next investigated the role of Grb2 binding in ETV6/FLT3-mediated leukemogenesis. Using coimmunoprecipitation assays, we demonstrated that Grb2 also binds to the tyrosine 314 and 354 of ETV6 of the ETV6/FLT3, in addition to the tyrosine 768, 955, and 969 of FLT3. Both ETV6/FLT3-Y314/354F and ETV6/FLT3-Y768/955/969F retained their interaction with Grb2 and induced rapidly fatal MPD when they were transduced into primary murine bone marrow cells. On the other hand, the ETV6/FLT3 mutant at all the binding sites of Grb2 (Y314/354/768/955/969F) significantly attenuated MPD development in mice. Simultaneous mutation of these 5 tyrosine residues completely abolished the binding of Grb2 and resulted in a marked decrease in the binding and phosphorylation of Gab2 and impaired activation of STAT5 and Akt in Ba/F3 cells. These results indicate that tyrosine 589 and 591 of FLT3 are dispensable for the ETV6/FLT3-induced MPD phenotype, and suggest that both ETV6 and FLT3 portions contribute to the ETV6/FLT3-mediated leukemogenesis by binding directly to Grb2. Our observations provide deep insights into the oncogenic signaling induced by active FLT3 mutants as well as provide a potential target for therapies. Disclosures: No relevant conflicts of interest to declare.

Functional Role of BAALC In Leukemogenesis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4194-4194
Author(s):  
Tobias Berg ◽  
Michael Heuser ◽  
Florian Kuchenbauer ◽  
Gyeongsin Park ◽  
Stephen Fung ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Cells ◽  
Myeloid Differentiation ◽  
Self Renewal ◽  
Murine Bone Marrow ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Marrow Cells

Abstract Abstract 4194 Cytogenetically normal acute myeloid leukemia (CN-AML) patients with high BAALC or MN1 expression have a poor prognosis. Whereas the oncogenic function of MN1 is well established, the functional role of BAALC in hematopoiesis is not known. We therefore compared the expression of BAALC and MN1 in 140 CN-AML patients by quantitative PCR. To further assess the impact of BAALC on leukemogenesis we used retroviral gene transfer into primary murine bone marrow cells and cells immortalized with NUP98-HOXD13 (ND13) and HOXA9. Transduced cells were assessed in vitro by colony forming assays and for their sensitivity to treatment with all-trans retinoic acid (ATRA). They were also evaluated by in vivo transplantation into lethally-irradiated mice. In the 140 CN-AML patients analyzed, the expression of BAALC and MN1 was highly correlated (R=0.71). Retroviral overexpression of MN1 or BAALC in the Hox gene-immortalized bone marrow cells did not cause upregulation of the other gene, suggesting that these genes do not regulate each other. In murine bone marrow cells BAALC did not immortalize the cells in vitro as assessed by serial replating of transduced cells in methylcellulose assays. Transplantation of transduced cells resulted in negligible engraftment of approximately 1 percent at 4 weeks after transplantation. However, co-transduction of BAALC into NUP98-HOXD13 cells (which are very sensitive to the treatment with all-trans retinoic acid) increased the 50 percent inhibitory concentration (IC50) of ATRA by 4.3-fold, suggesting a negative impact of BAALC on myeloid differentiation. We next evaluated whether the differentiation inhibiting effects of BAALC may cooperate with the self renewal-promoting effects of HOXA9 to induce leukemia in mice. Mice receiving transplants of murine bone marrow cells transduced with BAALC and HOXA9 developed myeloid leukemias with a median latency of 139.5 days that were characterized by leukocytosis, massively enlarged spleens (up to 1.02 g), anemia and thrombocytopenia. Infiltrations of myeloid cells were also found in liver, spleen, and kidney. The disease was transplantable into secondary animals. By Southern blot analysis we found one to two BAALC viral integrations per mouse, suggesting that clonal disease had developed from BAALC-transduced cells. We demonstrate for the first time that BAALC blocks myeloid differentiation and promotes leukemogenesis when combined with the self-renewal promoting oncogene HOXA9. Due to its prognostic and functional effects BAALC may become a valuable therapeutic target in leukemia patients. Disclosures: No relevant conflicts of interest to declare.

Non-Canonical NF-Kb Signaling Regulates Hematopoietic Stem Cell Self-Renewal and Microenvironment Interactions

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 859-859 ◽  
Author(s):  
Chen Zhao ◽  
Yan Xiu ◽  
John M Ashton ◽  
Lianping Xing ◽  
Yoshikazu Morita ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Cells ◽  
Conflicts Of Interest ◽  
Wild Type ◽  
Double Knockout ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Physiological Processes ◽  
Marrow Cells

Abstract Abstract 859 RelB and NF-kB2 are the main effectors of NF-kB non-canonical signaling and play critical roles in many physiological processes. However, their role in hematopoietic stem/progenitor cell (HSPC) maintenance has not been characterized. To investigate this, we generated RelB/NF-kB2 double-knockout (dKO) mice and found that dKO HSPCs have profoundly impaired engraftment and self-renewal activity after transplantation into wild-type recipients. Transplantation of wild-type bone marrow cells into dKO mice to assess the role of the dKO microenvironment showed that wild-type HSPCs cycled more rapidly, were more abundant, and had developmental aberrancies: increased myeloid and decreased lymphoid lineages, similar to dKO HSPCs. Notably, when these wild-type cells were returned to normal hosts, these phenotypic changes were reversed, indicating a potent but transient phenotype conferred by the dKO microenvironment. However, dKO bone marrow stromal cell numbers were reduced, and bone-lining niche cells supported less HSPC expansion than controls. Further, increased dKO HSPC proliferation was associated with impaired expression of niche adhesion molecules by bone-lining cells and increased inflammatory cytokine expression by bone marrow cells. Thus, RelB/NF-kB2 signaling positively and intrinsically regulates HSPC self-renewal and maintains stromal/osteoblastic niches and negatively and extrinsically regulates HSPC expansion and lineage commitment through the marrow microenvironment. Disclosures: No relevant conflicts of interest to declare.

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